Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function

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dc.contributor.authorHemingway, Cheryl
dc.contributor.authorBerk, Maurice
dc.contributor.authorAnderson, Suzanne T
dc.contributor.authorWright, Victoria J
dc.contributor.authorHamilton, Shea
dc.contributor.authorEleftherohorinou, Hariklia
dc.contributor.authorGoldgof, Greg M
dc.contributor.authorHickman, Katy
dc.contributor.authorKampmann, Beate
dc.contributor.authorSchoeman, Johan
dc.contributor.authorEley, Brian
dc.contributor.authorBeatty, David
dc.contributor.authorPienaar, Sandra
dc.contributor.authorNicol, Mark P
dc.contributor.authorGriffiths, Michael J
dc.contributor.authorWaddell, Simon J
dc.contributor.authorNewton, Sandra M
dc.contributor.authorCoin, Lachlan J
dc.contributor.authorRelman, David A
dc.contributor.authorMontana, Giovanni
dc.contributor.authorLevin, Michael
dc.date.accessioned2021-10-08T07:15:53Z
dc.date.available2021-10-08T07:15:53Z
dc.date.issued2017
dc.description.abstractThe WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies.
dc.identifier.apacitationHemingway, C., Berk, M., Anderson, S. T., Wright, V. J., Hamilton, S., Eleftherohorinou, H., ... Levin, M. (2017). Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function. <i>PloS One</i>, 12(11), e0185973 - 177. http://hdl.handle.net/11427/34716en_ZA
dc.identifier.chicagocitationHemingway, Cheryl, Maurice Berk, Suzanne T Anderson, Victoria J Wright, Shea Hamilton, Hariklia Eleftherohorinou, Greg M Goldgof, et al "Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function." <i>PloS One</i> 12, 11. (2017): e0185973 - 177. http://hdl.handle.net/11427/34716en_ZA
dc.identifier.citationHemingway, C., Berk, M., Anderson, S.T., Wright, V.J., Hamilton, S., Eleftherohorinou, H., Goldgof, G.M. & Hickman, K. et al. 2017. Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function. <i>PloS One.</i> 12(11):e0185973 - 177. http://hdl.handle.net/11427/34716en_ZA
dc.identifier.issn1932-6203
dc.identifier.ris TY - Journal Article AU - Hemingway, Cheryl AU - Berk, Maurice AU - Anderson, Suzanne T AU - Wright, Victoria J AU - Hamilton, Shea AU - Eleftherohorinou, Hariklia AU - Goldgof, Greg M AU - Hickman, Katy AU - Kampmann, Beate AU - Schoeman, Johan AU - Eley, Brian AU - Beatty, David AU - Pienaar, Sandra AU - Nicol, Mark P AU - Griffiths, Michael J AU - Waddell, Simon J AU - Newton, Sandra M AU - Coin, Lachlan J AU - Relman, David A AU - Montana, Giovanni AU - Levin, Michael AB - The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies. DA - 2017 DB - OpenUCT DP - University of Cape Town IS - 11 J1 - PloS One LK - https://open.uct.ac.za PY - 2017 SM - 1932-6203 T1 - Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function TI - Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function UR - http://hdl.handle.net/11427/34716 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/34716
dc.identifier.vancouvercitationHemingway C, Berk M, Anderson ST, Wright VJ, Hamilton S, Eleftherohorinou H, et al. Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function. PloS One. 2017;12(11):e0185973 - 177. http://hdl.handle.net/11427/34716.en_ZA
dc.language.isoeng
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicine
dc.publisher.facultyFaculty of Health Sciences
dc.sourcePloS One
dc.source.journalissue11
dc.source.journalvolume12
dc.source.paginatione0185973 - 177
dc.source.urihttps://dx.doi.org/10.1371/journal.pone.0185973
dc.subject.otherAdolescent
dc.subject.otherCase-Control Studies
dc.subject.otherChild
dc.subject.otherChild, Preschool
dc.subject.otherCohort Studies
dc.subject.otherCytokines
dc.subject.otherFemale
dc.subject.otherGene Expression Profiling
dc.subject.otherHumans
dc.subject.otherMale
dc.subject.otherRNA, Messenger
dc.subject.otherReverse Transcriptase Polymerase Chain Reaction
dc.subject.otherT-Lymphocytes
dc.subject.otherTuberculosis
dc.subject.otherCytokines
dc.subject.otherRNA, Messenger
dc.titleChildhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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